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Depletion of cardiac norepinephrine but not brain catecholamines by MPTP-N-oxide in mice
S K Hemrick-Luecke1, D W Robertson, R W Fuller
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
Abstract:
After a single dose in mice, MPTP-N-oxide caused a dose-dependent depletion of cardiac norepinephrine which was similar although less pronounced than that caused by MPTP itself. After repeated daily doses, MPTP-N-oxide depleted cardiac norepinephrine, but did not deplete norepinephrine in the frontal cortex or dopamine in the striatum of mice. MPTP-N-oxide differed from MPTP, which depleted cardiac norepinephrine, cortical norepinephrine and striatal dopamine after repeated daily doses, but was similar to MPP+, another metabolite of MPTP, which depleted only cardiac norepinephrine. These data suggest that MPTP-N-oxide may contribute to the peripheral catecholamine-depleting effects after MPTP injection.
Insights
MPTP-N-oxide, a metabolite of MPTP, depletes cardiac norepinephrine in mice, similar to MPP+. Unlike MPTP, it does not affect brain neurotransmitters, suggesting a role in peripheral effects.
Area of Science:
- Neuroscience
- Toxicology
- Pharmacology
Background:
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin known to cause Parkinsonism in humans and animals.
- MPTP is metabolized to MPP+ (1-methyl-4-phenylpyridinium), the active toxic species, and other metabolites like MPTP-N-oxide.
- The specific contribution of MPTP-N-oxide to the overall toxicity and neurochemical effects of MPTP remains incompletely understood.
Purpose of the Study:
- To investigate the effects of MPTP-N-oxide on catecholamine levels in different tissues following acute and repeated administration in mice.
- To compare the neurochemical effects of MPTP-N-oxide with those of MPTP and its metabolite MPP+.
- To determine if MPTP-N-oxide contributes to the peripheral or central catecholamine depletion associated with MPTP exposure.
Main Methods:
- Mice were administered single or repeated daily doses of MPTP-N-oxide, MPTP, or MPP+.
- Cardiac norepinephrine, frontal cortex norepinephrine, and striatal dopamine levels were measured after treatment.
- Dose-dependent effects and tissue-specific depletions were analyzed.
Main Results:
- A single dose of MPTP-N-oxide caused a dose-dependent depletion of cardiac norepinephrine, less pronounced than MPTP.
- Repeated daily doses of MPTP-N-oxide depleted cardiac norepinephrine but did not affect norepinephrine in the frontal cortex or dopamine in the striatum.
- MPTP-N-oxide's effects were similar to MPP+, which also only depleted cardiac norepinephrine, contrasting with MPTP's broader depletion of cardiac and brain catecholamines.
Conclusions:
- MPTP-N-oxide primarily affects peripheral catecholamine levels, specifically cardiac norepinephrine.
- The neurochemical profile of MPTP-N-oxide differs significantly from MPTP, indicating it is not the primary driver of central neurotoxicity.
- These findings suggest MPTP-N-oxide may contribute to the peripheral catecholamine-depleting effects observed after MPTP administration.